Thus far, knowledge about abnormalities of the hypothalamic-pituitary-adreno-cortical (HYPAC) axis such as those identified by the dexamethasone suppression test (DST) have had only limited impact on the clinical care and quality of life of individuals suffering from psychiatric depression. In order for tests of HYPAC function to be useful to patients, the tests must show clinically significant (and not just statistically significant) association with such factors as risk of depression, etiology, response to alternative treatments and long-term prognosis. By these criteria, new tests of HYPAC function are needed. Our recent studies of depressed patients indicate that the DST presents a static picture of a larger more dynamic derangement of the HYPAC axis. With continued funding we intend to examine the clinical implications and refine several measures of HYPAC function which appear to be more sensitive and less state-dependent than the DST. These measures include timing of cortisol nadir, level and ultradian pattern of ACTH and cortisol, cortisol response to endogenous ACTH, and resistance to insulin-induced hypoglycemia. The basic strategy is to examine how therapeutic interventions known to affect the course of depression act on the dynamics of the HYPAC system while simultaneously examining how response to several agents known to perturb the HYPAC system relate to course and subtype of depression. The first element of this strategy will use a protocol in which ACTH and cortisol are sampled every 20 minutes over a period of 24 hours. Patients will be studied before and after treatment with tricyclic antidepressants, electroconvulsive treatment or 36 hours of sleep deprivation. A new rate-dependent suppression test will also be used. The second element of the strategy includes the examination of the effects of several ACTH perturbation tests, including the administration of fenfluramine, insulin-induced hypoglycemia and vasopressin, which each stimulate ACTH release by different mechanisms. Previous studies suggest that response to insulin may be both state-independent and related to familial subtype.